Summary of work: As part of our program of research on early markers of Alzheimers disease, we are performing serial magnetic resonance imaging (MRI), including measures of vascular changes, positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early preclinical predictors of cognitive change and impairment, including Alzheimer's disease (AD). Neuroimaging evaluations of BLSA participants began in 1994 with approximately 160 individuals aged 55-85 at enrollment. We continue longitudinal testing of older participants and evaluation of new participants, including MRI and neuropsychological assessments of participants younger than 55 years old. Since 2009, we have expanded MRI assessments to a larger portion of the BLSA with more than 1000 individuals receiving MRI scans and concurrent cognitive assessments. For a subsample aged 55 and older, we performed PET measurements of cerebral blood flow, followed by a PET scan using 11-C-Pittsburgh Compound B (PiB) to measure in vivo amyloid deposition. Over the last 2 years we expanded our amyloid imaging studies from 50 scans per year to 70 scans per year through Alzheimer's disease funding initiatives. In addition, we initiated Tau PET (AV-1451) studies of BLSA participants receiving PET amyloid scans (separate annual report). Our progress includes continued acquisition of new neuroimaging assessments and continued analysis of existing data and methods development. We use neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in cognitive and brain aging, genetic, metabolic, and inflammatory risk factors, and the effects of sex steroid and other hormones. An understanding of these brain-behavior associations and early detection of accelerated brain changes during the preclinical or asymptomatic stage of disease will be critical in identifying individuals likely to benefit from interventions if a successful treatment for prevention or delaying onset of disease is available. Over the last year we have published a number of papers, including demonstrations that elevated markers of inflammation are associated with longitudinal changes in regional cerebral blood flow measured by PET (Warren et al, 2018) and that rates of amyloid-beta accumulation are greater in amyloid positive individuals who also have metabolic syndrome (Gomez et al, 2018). We have used multimodal imaging with measures of brain structure and resting state fMRI connectivity to characterize the heterogeneity of structural and functional MR imaging patterns in five groups of individuals demonstrating patterns of advanced aging versus a group of resilient agers (Eavani et al, 2018). We have also investigated associations between regional white matter lesion volumes, representing 4 clusters of distinct anatomic distribution, and clinical and cognitive characteristics in BLSA participants (Habes et al, 2018). We have used the rich data available from participants receiving amyloid PET and structural MRI scans in combination with serial cognitive assessments to investigate the independent and joint effects of amyloid pathology, a hallmark Alzheimers neuropathology, and neurodegeneration, measured by hippocampal atrophy, on changes in memory and other cognitive domains (Bilgel et al, 2018). We categorized 171 cognitively normal BLSA participants (562 cognitive assessments, 3.7 years follow-up) based on dichotomous amyloid pathology (A) and hippocampal neurodegeneration (N) status at baseline: A-N-, A+N-, A-N+, A+N+. We conducted linear mixed effects analyses to assess cross-sectional and longitudinal trends in cognitive test z-scores by amyloid and neurodegeneration group. Individuals with amyloidosis or hippocampal atrophy had steeper longitudinal declines in verbal episodic memory and learning compared to those with neither condition. Among individuals with hippocampal atrophy, amyloid positivity was associated with steeper declines in verbal memory, visual memory, language, and mental status. Similarly, among individuals with amyloidosis, hippocampal atrophy was associated with steeper declines in verbal memory, visual memory, language, and mental status. Presence of both amyloidosis and hippocampal atrophy was associated with greater declines than would be expected by their additive contributions in visual memory, language, and mental status. Neither amyloidosis nor hippocampal atrophy was predictive of declines in executive function, processing speed, or visuospatial ability. Our results suggest that both amyloid pathology and neurodegeneration have disadvantageous, in part synergistic, effects on prospective cognition. These cognitive effects are detectable early among cognitively normal individuals with amyloidosis, who are in preclinical stages of Alzheimer's disease and highlight the importance of early intervention to target both amyloidosis and atrophy to preserve cognitive function before further damage occurs. Methodological Developments. We have continued to optimize our approach for MRI volumetric analysis. We have used the MUSE analysis pipeline to harmonize MRI volumetric data over more than 20 years, allowing analysis of predictors of neurodegeneration. This approach was validated for MRI data acquired across different field strengths and vendors (Erus et al, 2018). In addition to these selected highlights, we have a number of manuscripts at various stages of review and development, including papers describing accelerated MRI-assessed brain volume loss in individuals who subsequently develop cognitive impairment, sex differences in volume loss, and brain volume changes in participants with hearing loss.